This work is directed towards obtaining a better understanding of how the antigen receptor on B lymphocytes contributes to the development of different peripheral B cell populations and to the function of B lymphocytes in humoral immunity. Molecules that regulate signaling via the antigen receptor may contribute not only to the development and function of B lymphocytes, but may also be players in the genesis of lymphomas and leukemias, and may contribute to the development of certain autoimmune disorders. In these proposed studies, the contributions of a specific sialic acid O-acetylesterase to the strength of B cell antigen receptor signaling, to the development of marginal zone B cells, and to the emergence of a recirculating perisinusoidal bone marrow B cell population will be examined. In the first specific aim studies are proposed to examine whether luminal/lysosomal sialyl O-acetylesterase alters antigen receptor signal strength by acetylating sialic acid containing ligands for CD22, and thereby contributes to a major reduction in marginal zone B cells in mice lacking this enzyme. The regulation of luminal/lysosomal sialyl O- acetylesterase expression and activity during B cell development and B cell activation will be examined. In the second specific aim studies are proposed to examine why the absence of this sialyl-O-acetylesterase results in the loss of recirculating follicular B cells in the bone marrow. The cell intrinsic nature of this defect will be examined and molecular mechanisms involved in retaining mature B cells in the bone marrow will be explored. In this study we will ask how certain immune cells develop and are activated, and the processes by which cells are invited to reside in the bone marrow will also be examined. Insights obtained may be of importance in leukemias and and in autoimmune diseases like lupus.